Tranexamic acid formulations

ABSTRACT

Disclosed are modified release oral tranexamic acid formulations and methods of treatment therewith.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/620,226, filed Sep. 14, 2012 which is pending, which is acontinuation of U.S. patent application Ser. No. 12/228,489 filed onAug. 13, 2008, now U.S. Pat. No. 8,273,795, which is a continuation ofU.S. patent application Ser. No. 11/072,194 filed Mar. 4, 2005, whichclaims the benefit of U.S. Provisional Application No. 60/550,113, filedMar. 4, 2004, and U.S. Provisional Application No. 60/592,885, filedJul. 30, 2004. The entire disclosure of each of the prior applicationsis hereby incorporated herein by reference.

FIELD OF THE INVENTION

The invention is directed to modified release oral tranexamic acidformulations that preferably minimize or eliminate undesirable sideeffects and methods of treatment with these formulations.

BACKGROUND OF THE INVENTION

Tranexamic acid (trans-4-(aminomethyl) cyclohexanecarboxylic acid,Cyklokapron® (Pfizer) is an antifibrinolytic agent. That is, it helps toprevent lysis or dissolution of a fibrin clot which forms in the normalphysiologic process of hemostasis. Its mechanism of action is as acompetitive inhibitor of plasminogen activation, and as a noncompetitiveinhibitor of plasmin; both plasminogen and plasmin are activators offibrinolysis and active clot-lysing agents. Tranexamic acid thus helpsto stabilize fibrin clots, which in turn maintains coagulation and helpsto control bleeding.

Tranexamic acid is used to control excess bleeding, for example, excessbleeding that occurs during dental procedures in hemophiliacs and forheavy bleeding during menstruation (menorrhagia). Women suffering frommenorrhagia are typically treated orally with 500 mg tranexamic acidtablets administered three or four times daily with a total daily doseranging from 3 grams/day (two tablets every eight hours) to 6 grams/day(three tablets every six hours). However, this treatment may causeadverse gastrointestinal reactions, including nausea, vomiting,diarrhea, and cramping, etc. These gastrointestinal side effects are dueto the quantity of tranexamic acid and/or rapid rate of release oftranexamic acid into the stomach with each dose, as well as the largequantity of excipients used in the tablet formulation that areintroduced into the stomach. Such side effects, in addition to thecramping, bloating, pain, and other symptoms that may accompany menses,are undesirable, and a formulation of tranexamic acid is needed whichwill reduce or eliminate these side effects.

SUMMARY OF THE INVENTION

Formulations of tranexamic acid which minimize or eliminate theundesirable gastrointestinal side effects in patients on oral tranexamicacid therapy, e.g. women treated for menorrhagia (heavy menstrualbleeding) are disclosed. The present invention is directed in part to amodified release formulation, formulated so that the release oftranexamic acid thereof from the dosage form occurs in a designedfashion to prevent a bolus of tranexamic acid being introduced into thestomach and available for dissolution in the gastric contents. Suchmodified release formulations reduce the concentration of tranexamicacid dissolved in the stomach contents such as e.g., preventing a largebolus of tranexamic acid being introduced in the stomach. The beneficialeffect of this reduced tranexamic acid concentration is to lower theamount of tranexamic acid in the gastric contents so that there arefewer adverse effects with tranexamic acid therapy. This reduction inadverse effects preferably results in improved patient compliance withtherapy, because preferably patients will not intentionally miss takinga dose to avoid these adverse side effects. Physicians will alsopreferably be more likely to initiate and maintain tranexamic acidtreatment for their patients because of the reduced patient complaints.

It is an object of the invention to provide an oral dosage formcomprising tranexamic acid which is suitable for administration on a twoor three times a day basis to humans.

It is a further object of the invention to provide a modified releaseoral dosage form comprising tranexamic acid and a modified releasematerial which provides for the modified release of the tranexamic acidand is suitable for administration on a two or three times a day basis.

It is a further object of certain embodiments of the present inventionto provide a modified release oral dosage form comprising tranexamicacid and a modified release material which minimizes or eliminates theundesirable gastrointestinal side effects in patients on oral tranexamicacid therapy while maintaining or improving the therapeutic effect oftranexamic acid.

It is a further object of certain embodiments of the present inventionto provide a method of treating a patient suffering from heavy menstrualbleeding (menorrhagia) by orally administering to the patient one ormore dosage forms comprising tranexamic acid and a modified releasematerial which provide(s) for therapeutically effective levels oftranexamic acid suitable for two or three times a day administration.

The above advantages and objects and others can be achieved by virtue ofthe present invention which is directed in part to a modified releaseoral dosage form comprising tranexamic acid or a pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis; saiddosage form providing an in-vitro dissolution release rate of thetranexamic acid or pharmaceutically acceptable salt thereof, whenmeasured by a USP 27 Apparatus Type II Paddle Method @50 RPM in 900 mlwater at 370.5° C., of less than about 70% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutesand about 100% by weight of said tranexamic acid or pharmaceuticallyacceptable salt thereof released by about 120 minutes.

In certain embodiments, the present invention is directed to a method oftreating a patient in need of tranexamic acid or pharmaceuticallyacceptable salt thereof therapy comprising administering to the patientabout 1300 mg of tranexamic acid or pharmaceutically acceptable saltthereof in at least one oral dosage form comprising said tranexamic acidor pharmaceutically acceptable salt thereof and a modified releasematerial which provides a mean maximum plasma concentration (C_(max)) oftranexamic acid of from about 5 to about 17.5 mcg/ml, preferably fromabout 6.5 to about 15 mcg/ml, more preferably from about 9 to about 14.5mcg/ml after single dose oral administration to humans.

In certain embodiments, the invention is further directed to a method oftreating a patient in need of tranexamic acid or pharmaceuticallyacceptable salt thereof therapy comprising administering to the patientabout 1300 mg of tranexamic acid or pharmaceutically acceptable saltthereof in at least one oral dosage form comprising said tranexamic acidor pharmaceutically acceptable salt thereof and a modified releasematerial which provides a mean maximum plasma concentration (C_(max)) oftranexamic acid of from about 5 to about 25 mcg/ml, preferably fromabout 10 to about 20 mcg/ml, more preferably from about 12.5 to about17.5 mcg/ml, most preferably about 15 to about 17 mcg/ml after steadystate oral administration to humans.

In certain embodiments, the modified release oral dosage form of thepresent invention provides a mean T_(max) of tranexamic acid at fromabout 1 to about 5.5 hours, preferably at from about 2 to about 4 hours,more preferably at from about 2 to about 3.5 hours after oraladministration of the dosage form to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides a dissolution release rate in-vitro of thetranexamic acid or pharmaceutically acceptable salt thereof whenmeasured by the USP 27 Apparatus Type II Paddle Method (50 RPM in 900 mlwater at 37±0.5° C. of less than about 40% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 15 minutes,less than about 70% by weight tranexamic acid or pharmaceuticallyacceptable salt thereof released at about 45 minutes, and not less than50% by weight tranexamic acid or pharmaceutically acceptable saltthereof released at about 90 minutes.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides a dissolution release rate in-vitro of thetranexamic acid or pharmaceutically acceptable salt thereof whenmeasured by the USP 27 Apparatus Type II Paddle Method @50 RPM in 900 mlwater at 37±0.5° C. of about 0% to about 40% by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 15minutes, from about 20% to about 60% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 30 minutes,from about 40% to about 65% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 50% to about 90% by weight tranexamic acid orpharmaceutically acceptable salt thereof release at about 60 minutes,and not less than 60% by weight tranexamic acid or pharmaceuticallyacceptable salt thereof released at about 90 minutes.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material, which providesfor a bioavailability of tranexamic acid of greater than 40%, from about41% to about 60%, preferably from about 42% to about 50%, morepreferably about 45% after oral administration to humans

In certain embodiments, the present invention is further directed to amodified release oral dosage form comprising from about 585 to about 715mg of tranexamic acid or pharmaceutically acceptable salt thereof,preferably about 650 mg of tranexamic acid or pharmaceuticallyacceptable salt thereof, and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis.

In certain embodiments, the present invention is directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis, thedosage form providing a reduction of at least one side effect selectedfrom the group consisting of headache, nausea, vomiting, diarrhea,constipation, cramping, bloating, and combinations thereof, as comparedto an equivalent amount of tranexamic acid or pharmaceuticallyacceptable salt thereof in an immediate release oral dosage form whenadministered across a patient population.

In certain embodiments, the present invention is directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release excipient, said dosageform providing for the release of the tranexamic acid orpharmaceutically acceptable salt thereof which is slower than animmediate release oral dosage form and faster than a controlled releaseoral dosage form, such that the modified release oral dosage form issuitable for administration two or three times a day.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for oral administration on athree times a day basis, and the dosage form providing a mean maximumplasma concentration (C_(max)) of tranexamic acid of from about 5 toabout 17.5 mcg/ml, preferably from about 6.5 to about 15 mcg/ml, morepreferably from about 9 to about 14.5 mcg/ml per 1300 mg tranexamic acidafter single dose oral administration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for oral administration on atwice a day basis, and the dosage form providing a mean maximum plasmaconcentration (C_(max)) of tranexamic acid of from about 5 to about 40mcg/ml, preferably from about 10 to about 30 mcg/ml per 1950 mgtranexamic acid after single dose oral administration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for oral administration on athree times a day basis, and the dosage form providing a mean plasmaconcentration of tranexamic acid of from about 5 to about 25 mcg/ml,preferably from about 7.5 to about 15 mcg/ml, more preferably from about8 to about 10 mcg/ml, most preferably about 9 mcg/ml per 1300 mgtranexamic acid after steady state oral administration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and a modified releasematerial, the dosage form being suitable for administration on a threetimes a day basis, and the dosage form providing a mean maximum plasmaconcentration (C_(max)) of tranexamic acid of from about 5 to about 25mcg/ml, preferably from about 10 to about 20 mcg/ml, more preferablyfrom about 12.5 to about 17.5 mcg/ml, most preferably about 15 to about17 mcg/ml per 1300 mg tranexamic acid after steady state oraladministration to humans.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and an modified releasematerial, the dosage form being suitable for administration on a threetimes a day basis, and the dosage form providing a mean plasma troughconcentration of tranexamic acid or pharmaceutically acceptable saltthereof of from about 2 to about 10 mcg/ml, preferably from about 3 toabout 7.5 mcg/ml, more preferably about 4 to about 7 mcg/ml, mostpreferably about 5 to about 6 mcg/ml per 1300 mg tranexamic acid orafter steady state oral administration to humans.

In certain embodiments, the invention is further directed to a method oftreating a patient with a therapeutically effective amount of tranexamicacid or pharmaceutically acceptable salt thereof comprisingadministering to the patient two dosage forms of the present invention,each dosage form comprising from about 585 mg to about 715 mg oftranexamic acid or pharmaceutically acceptable salt thereof, preferablyabout 650 mg tranexamic acid or pharmaceutically acceptable saltthereof, and a modified release material such that the dosage form issuitable for oral administration on a three times a day basis.

In certain embodiments, the invention is further directed to a method oftreating a patient with a therapeutically effective amount of tranexamicacid or pharmaceutically acceptable salt thereof comprisingadministering to the patient three dosage forms of the presentinvention, each dosage form comprising from about 585 mg to about 715mg, preferably about 650 mg tranexamic acid or pharmaceuticallyacceptable salt thereof, and a modified release material such that thedosage form is suitable for oral administration on a twice a day basis.

In certain embodiments, the invention is directed to a dose oftranexamic acid or pharmaceutically acceptable salt thereof comprisingtwo unit dosage forms of a modified release formulation, each unitdosage form of said modified release formulation comprising from about585 mg to about 715 mg, preferably about 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof, and a modified releasematerial which provides for the release of the tranexamic acid orpharmaceutically acceptable salt thereof from the dosage form such thatthe dose provides a therapeutic effect when administered three times aday.

In certain embodiments, the invention is directed to a dose oftranexamic acid comprising three unit dosage forms of a modified releaseformulation, each unit dosage form of said modified release formulationcomprising from about 585 mg to about 715 mg, preferably about 650 mg oftranexamic acid or pharmaceutically acceptable salt thereof, and amodified release material which provides for the release of thetranexamic acid or pharmaceutically acceptable salt thereof from thedosage form such that the dose provides a therapeutic effect whenadministered twice a day.

In certain preferred embodiments, the invention is further directed to amodified release oral dosage form including tranexamic acid orpharmaceutically acceptable salt thereof and a modified release materialwhich provides for the modified release of the tranexamic acid orpharmaceutically acceptable salt thereof from the dosage form such thatthe dosage form is suitable for administration on a two or three times aday basis and the dosage form provides a dissolution release ratein-vitro of the tranexamic acid or pharmaceutically acceptable saltthereof when measured by the USP 27 Apparatus Type II Paddle Method @50RPM in 900 ml water at 37±0.5° C. of about 0% to about 40% by weighttranexamic acid or pharmaceutically acceptable salt thereof released atabout 15 minutes, from about 20% to about 60% by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 30minutes, from about 40% to about 80% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 50% to about 95% by weight tranexamic acid orpharmaceutically acceptable salt thereof release at about 60 minutes,and not less than about 60% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 90 minutes.

In certain preferred embodiments, the invention is further directed to amodified release oral dosage form including tranexamic acid orpharmaceutically acceptable salt thereof and a modified release materialwhich provides for the modified release of the tranexamic acid orpharmaceutically acceptable salt thereof from the dosage form such thatthe dosage form is suitable for administration on a two or three times aday basis and the dosage form provides a dissolution release ratein-vitro of the tranexamic acid or pharmaceutically acceptable saltthereof when measured by the USP 27 Apparatus Type II Paddle Method @50RPM in 900 ml water at 37±0.5° C. of about 14% to about 22% by weighttranexamic acid or pharmaceutically acceptable salt thereof released atabout 15 minutes, from about 32% to about 50% by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 30minutes, from about 47% to about 71% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 45 minutes,from about 61% to about 92% by weight tranexamic acid orpharmaceutically acceptable salt thereof release at about 60 minutes,and from about 79% to about 100% by weight tranexamic acid orpharmaceutically acceptable salt thereof released at about 90 minutes.

In certain embodiments, the invention is directed to a modified releaseoral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and an effective amount of a modified releaseexcipient such that the dosage form releases from about 10% to about 25%by weight tranexamic acid or pharmaceutically acceptable salt thereofevery 15 minutes when measured in vitro utilizing the USP 27 ApparatusType II Paddle Method @50 RPM in 900 ml water at 37±0.5° C. In certainpreferred embodiments, the dosage form releases about 18% to about 23%by weight tranexamic acid or pharmaceutically acceptable salt thereofevery 15 minutes when measured in vitro utilizing the USP 27 ApparatusType II Paddle Method @50 RPM in 900 ml water at 37±0.5° C. Mostpreferably, the dosage form releases about 100% of said tranexamic acidor pharmaceutically acceptable salt thereof within about 120 minuteswhen measured in vitro utilizing the USP 27 Apparatus Type II PaddleMethod @50 RPM in 900 ml water at 37±0.5° C. In certain embodiments, thedosage form releases about 1% of said tranexamic acid orpharmaceutically acceptable salt thereof every minute when measured invitro utilizing the USP 27 Apparatus Type II Paddle Method @50 RPM in900 ml water at 37±0.5° C.

In certain preferred embodiments, the modified release oral dosage formof the invention further provides a mean transit time of said tranexamicacid of 7.70-0.72 hours when administered across a patient population.

In certain preferred embodiments, the modified release oral dosage formof the invention further provides a mean absorption time of saidtranexamic acid of 4.18 f 0.70 hours when administered across a patientpopulation.

In certain further embodiments, the modified release oral dosage form ofthe present invention provides confidence intervals derived fromln-transformed pharmacokinetic kinetic parameters AUC_(0-t), AUC_(inf)and C_(max) for tranexamic acid in plasma which are within a 80-125%range of an immediate release formulation including an equivalent amountof tranexamic acid when administered across a patient population underfasted conditions.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides less than about 20 percent incidence ofheadache as a side effect after single dose oral administration across apatient population.

In certain embodiments, the invention is further directed to a modifiedrelease oral dosage form comprising tranexamic acid or pharmaceuticallyacceptable salt thereof and a modified release material which providesfor the modified release of the tranexamic acid or pharmaceuticallyacceptable salt thereof from the dosage form such that the dosage formis suitable for administration on a two or three times a day basis andthe dosage form provides less than about 10 percent incidence of nauseaas a side effect when administered across a patient population, lessthan about 7 percent incidence of nausea when administered across apatient population, preferable less than about 5 percent incidence ofnausea as a side effect when administered across a patient population,more preferably less than about 2 percent incidence of nausea as a sideeffect after single dose oral administration across a patientpopulation.

In certain embodiments, the modified release oral dosage form of thepresent invention provides less CNS side effects (e.g., headache), lessGI side effects (e.g., nausea), or combination thereof in comparison toan equivalent amount of tranexamic acid or pharmaceutically acceptablesalt thereof in an immediate release formulation when administeredacross a patient population. Additionally or alternatively, in certainembodiments the dosage form provides less CNS side effects (e.g.,headache), less GI side effects (e.g., nausea), or combination thereofin comparison to a therapeutically equivalent amount of tranexamic acidadministered intravenously in five minutes or less across a patientpopulation.

In certain embodiments, the modified release oral dosage form of thepresent invention provides for the reduction of at least one side effectas compared to an immediate release oral dosage form including anequivalent amount of tranexamic acid or pharmaceutically acceptable saltthereof, when the immediate release dosage form is administered across asame or different population of patients as said modified release dosageform, and wherein said immediate release dosage form releases all ofsaid tranexamic acid or pharmaceutically acceptable salt thereof withinabout 45 minutes when measured in vitro utilizing the USP 27 ApparatusType II Paddle Method (50 RPM in 900 ml water at 370.5° C. Such sideeffects can be for example, headache, nausea, vomiting, diarrhea,constipation, cramping, bloating, and combinations thereof

In certain embodiments, the modified release oral dosage form of thepresent invention provides a mean transit time of tranexamic acid whichis at least about 20 minutes longer, preferably about 30 minutes longer,than an immediate release formulation including an equivalent amount oftranexamic acid when administered across a patient population.

In certain embodiments, the dosage form of the present inventionprovides a mean absorption time of tranexamic acid which is at leastabout 20 minutes longer, preferably about 30 minutes longer, than animmediate release formulation including an equivalent amount oftranexamic acid when administered across a patient population.

In certain preferred embodiments, the therapeutically effective dose ofthe tranexamic acid or pharmaceutically acceptable salt thereof isprovided via the administration of two or more dosage units. Forexample, if the dosage unit comprises 650 mg of tranexamic acid orpharmaceutically acceptable salt thereof and the dose for administrationis about 1300 mg then two dosage units would be administered to apatient in need of such treatment, or for example, when the dose foradministration is 1950 mg, three dosage units would be administered.

In certain preferred embodiments, the invention is further directed to amethod of treating a patient with one or more modified release oraldosage forms comprising tranexamic acid or pharmaceutically acceptablesalt thereof and a modified release material, wherein the oral dosageform provides a therapeutically effective plasma level of tranexamicacid or pharmaceutically acceptable salt thereof in accordance with athree times a day (TID) dosing schedule, and the therapeuticallyeffective dose administered comprises about 1300 mg of tranexamic acidor pharmaceutically acceptable salt thereof.

In certain preferred embodiments, the invention is further directed to amethod of treating a patient with one or more modified release oraldosage forms comprising tranexamic acid or pharmaceutically acceptablesalt thereof and a modified release material, wherein the oral dosageform provides a therapeutically effective plasma level of tranexamicacid or pharmaceutically acceptable salt thereof in accordance with atwice a day (BID) dosing schedule, and the therapeutically effectivedose administered comprises about 1950 mg of tranexamic acid orpharmaceutically acceptable salt thereof.

In certain embodiments, the invention is directed to a method ofproviding a tranexamic acid plasma concentration within the range ofabout 5 mcg/mL to about 15 mcg/mL by administration of a modifiedrelease formulation of the present invention comprising tranexamic acidor pharmaceutically acceptable salt thereof and a modified releasematerial on a three times a day basis to a patient in need of tranexamicacid or pharmaceutically acceptable salt thereof treatment.

In certain embodiments, the invention is further directed to a method oftreating a human patient with heavy menstrual bleeding (e.g.,menorrhagia) comprising administering about 1300 mg of tranexamic acidor pharmaceutically acceptable salt thereof on a three times a day basisto the human patient to provide a tranexamic acid or pharmaceuticallyacceptable salt thereof plasma concentration within the range of about 5mcg/mL to about 15 mcg/mL after steady state oral administration to ahuman patient.

In certain embodiments, the invention is directed to a method oftreating a patient suffering from menorrhagia, conization of the cervix,epistaxis, hyphema, hereditary angioneurotic edema, a patient with ablood coagulation disorder undergoing dental surgery, combinationsthereof, and the like, by administering at least one dosage form of thepresent invention to the patient in need in tranexamic acid orpharmaceutically acceptable salt thereof therapy.

In certain embodiments, the invention is directed to a method oftreating heavy menstrual bleeding with a therapeutically effective doseof at least one oral formulation of the present invention comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material wherein the menstrual blood loss per menstrualcycle is reduced by at least about 10 ml, preferably at least about 20ml, more preferably at least about 40 ml. In a most preferred embodimentthe menstrual blood loss per menstrual cycle is reduced by greater thanor equal to about 50 ml.

In certain embodiments, the invention is directed to a method oftreating heavy menstrual bleeding with a therapeutically effective doseof at least one oral formulation of the present invention comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material which upon oral administration to a humanfemale reduces the blood loss per menstrual cycle by about 35 ml toabout 200 ml, preferably about 40 ml to about 175 ml, more preferablyfrom about 50 ml to about 150 ml.

In certain embodiments, the invention is further directed to a method oftreating heavy menstrual bleeding with a therapeutically effective doseof at least one oral formulation of the present invention comprisingtranexamic acid or pharmaceutically acceptable salt thereof and amodified release material which upon oral administration to a humanfemale reduces the blood loss per menstrual cycle by about 20% to 100%,preferably from about 20% to about 70%.

The menstrual blood loss can be measured by procedures known in the art.For example, in certain embodiments, the menstrual blood loss can bedetermined by a procedure described by (i) L. Hallbert, et al. in“Determination of Menstrual Blood Loss”, Scandinav. J. Clin. & Lab.Investigation, 244-248, 16, 1964, wherein the procedure is performed byextracting the menstrual blood from vaginal tampons and towels with asodium hydroxide solution, converting heme chromogens to alkalinehematin, which is determined spectrophotometrically; or (ii) themenstrual blood loss can be determined by a procedure described by J.Newton, M. D., et al., in “A Rapid Method for Measuring Menstrual BloodLoss Using Automatic Extraction.”, Contraception, 269-282, September1977, Vol. 16, No. 3, wherein the procedure is based upon the formationof alkaline haematin after the blood has been extracted from vaginaltampons and sanitary towels by an automatic Stomacher Lab-Blender. Thedisclosures of the aforementioned articles are hereby incorporated byreference in their entireties.

In certain embodiments, the modified release material may beincorporated in a coating applied onto e.g., a tablet comprising thetranexamic acid or pharmaceutically acceptable salt thereof, may beincorporated into a matrix with the tranexamic acid or pharmaceuticallyacceptable salt thereof, or a combination thereof. For example, incertain preferred embodiments, the modified release material is acontrolled release material such as a gel-forming or hydratable polymerwhich is added to e.g., a matrix composition comprising the tranexamicacid or pharmaceutically acceptable salt thereof.

In certain embodiments, the tranexamic acid for use in the methods andformulations of the present invention is in the form of apharmaceutically acceptable salt thereof. Such salt forms include forexample and without limitation the sodium salt, potassium salt, calciumsalt, magnesium salt and the like; as well as the hydrochloride,hydrobromide, sulfate, phosphate, formate, acetate, trifluoroacetate,maleate, tartrate, methanesulfonate, benzenesulfonate,p-toluenesulfonatemethanesulfonate salt forms, and the like. Preferablythe active ingredient for use in accordance with the present inventionis tranexamic acid.

An “immediate release oral dosage form” for purposes of the presentinvention is a dosage form which releases all of active ingredient(e.g., tranexamic acid) included therein within about 45 minutes whenmeasured in vitro utilizing the USP 27 Apparatus Type II Paddle Method@50 RPM in 900 ml water at 37±0.5° C.

A “modified release oral dosage form” for purposes of the presentinvention is an oral dosage form which releases the active ingredient(e.g., tranexamic acid) included therein in a manner that is slower thanan immediate release oral dosage form and faster than a controlledrelease oral dosage form, when the dosage forms include the same amountof active as the modified release oral dosage form. One definition ofthe terms “slower” and “faster” as used in this application is that theyare meant to represent a statistically significant difference at eachmeasured 15 minute interval after the start of in-vitro dissolution. Incertain preferred embodiments, the modified release oral dosage form ofthe present invention provides an in-vitro dissolution release rate oftranexamic acid or pharmaceutically acceptable salt thereof, whenmeasured by a USP 27 Apparatus Type II Paddle Method @50 RPM in 900 mlwater at 3740.5° C., of less than about 70%/e by weight tranexamic acidor pharmaceutically acceptable salt thereof released at about 45 minutesand about 100% by weight of said tranexamic acid or pharmaceuticallyacceptable salt thereof released by about 120 minutes.

A “controlled release oral dosage form” for purposes of the presentinvention is a dosage form which releases all of the active ingredient(e.g., tranexamic acid) included therein after about 4 hours or morewhen measured in vitro utilizing the USP 27 Apparatus Type II PaddleMethod @50 RPM in 900 ml water at 37±0.5° C.

The term “C_(max)” unless otherwise indicated is meant for purposes ofthe present invention to mean the maximum plasma concentration of amedicament achieved after single dose administration of a dosage form,or the maximum plasma concentration of a medicament achieved over adosing interval from multiple-doses at steady-state in accordance withthe present invention.

The term “T_(max)” is meant for purposes of the present invention tomean the elapsed time from administration of a dosage form to the timethe C_(max) of the medicament is achieved.

The term “steady state” means that the amount of the drug reaching thesystem is approximately the same as the amount of the drug leaving thesystem. Thus, at “steady-state”, the patient's body eliminates the drugat approximately the same rate that the drug becomes available to thepatient's system through absorption into the blood stream.

The term “mean” for purposes of the present invention, when used todefine a pharmacokinetic value (e.g., T_(max)), unless specifiedotherwise, represents the arithmetic mean value measured across apatient or subject population.

The term “three times a day (TID) basis” for purposes of the presentinvention, means that the dosage regimen is to be administered threetimes a day, preferably on a schedule of every 8 hours.

The term “mean transit time” is understood by those skilled in the artand means the time-point where 63.2% of the total AUC is attained afteroral administration, or 63.2% of the IV dose is eliminated, as describedin Applied Pharmacokinetics. Principles of Therapeutic Drug Monitoring,Second Edition (1986), edited by William E. Evans, et al., thedisclosure of which is hereby incorporated by reference in its entirety.

The term “mean absorption time” is understood by those skilled in theart and means a quantitative parameter which summarizes how long, onaverage, the drug molecule remains unabsorbed, i.e. persists in itsdosage form and in the gastrointestinal tract, also as described inApplied Pharmacokinetics, Principles of Therapeutic Drug Monitoring,Second Edition (1986), edited by William E. Evans, et al. Unlike theabsorption rate constants (ka) which can be skewed, the mean absorptiontimeis not affected by incomplete release of drug from its dosage form,irregular absorption, lag-time, mixed zero-order dissolution rates,changing GI motility, GI blood flow, first-pass effect, etc.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts concentration-time profiles for simulated administrationof the 1.3 g tranexamic acid modified release formulation of Example 1at a Q8H (every 8 hours) dosing schedule of 6:00 AM, 2:00 PM, 10:00 PMcomparing it with 1 g administered Q8H.

FIG. 2 depicts concentration-time profiles for simulated administrationof the 1.3 g tranexamic acid modified release formulation of Example 1at a TID (three times a day) dosing schedule of 8:00 AM, 2:00 PM, 8:00PM comparing it with 1 g administered TID.

FIG. 3 depicts mean plasma concentration-time profiles on a semi-logscale over 36 hours for the study of Example 4.

FIG. 4 depicts mean plasma concentration-time profiles on a linear scaleover 36 hours for the study of Example 4.

DETAILED DESCRIPTION

The dosage regimen typically listed for tranexamic acid in HMB (HeavyMenstrual Bleeding) therapy is 1-1.5 g per dose administered three-fourtimes a day at the onset of copious menstrual bleeding and continued forthe first 3-5 days of the menstrual cycle. However, the most frequentlyreported dosage regimen of tranexamic acid is an immediate release oralformulation in which 1 g tranexamic acid is administered four times aday (4 g per day) for HMB therapy outside of the US. Knowledge of thiscommon regimen is supported by a careful review of the randomizedcontrolled trials published in the medical literature, product labelingfrom other countries' regulatory authorities having the product approvedfor HMB therapy, utilization data from Sweden (Rybo 1991),correspondence and interviews with non-US clinicians having experiencewith the product. That regimen is currently the dosage being studied bythe US Center for Disease Control (CDC) in women with HMB associatedwith bleeding disorders.

The absolute bioavailability of tranexamic acid observed whenadministering the European commercial formulation (Cyklokapron, Kabi AB,Sweden Batch 90288; assay 499 mgm/tablet) to male subjects isapproximately 35% and its elimination correlates with renal creatinineclearance. Peak serum tranexamic acid concentrations occur approximately3 hours after the oral administration of a European immediate-releasetablet formulation (>85% dissolved at 15 minutes) (Pilbrant, et al.,Eur. J. Clin. Pharmacol, (1981)-20:65-72). By comparison, the in vivoabsorption profile observed with the European immediate-releaseformulation is slow and very gradual over 3 hours. Specifically,tranexamic acid serum concentrations are 9, 41, 73, 88 percent (withfood), and 22, 63, 85, and 98 percent (fasting) of maximal absorption at0.5, 1, 1.5 and 2 hours after a 2 g oral dose, respectively. Althoughnot wishing to be held to any specific theory, it is presentlyhypothesized that tranexamic acid oral absorption appears to becontrolled by a non-dissolution rate limited process, i.e. the rate andextent of oral absorption is a function of a transmembranepassage-limited process, in order to explain the disparity between thetime of product dissolution and relatively prolonged tmax (time toachieve the peak serum concentration).

Preferably, the goal of the formulation, dose strength and dosageregimen of the invention, is to provide HMB therapy which achieves fromabout 20% to 100% reduction in menstrual blood loss per menstrual cycle.In accordance with certain embodiments of the present invention, thepreferred tranexamic acid dose of 1.3 g every 8 hours is predicted toprovide an average serum tranexamic acid concentration comparable tothat produced by a 1 g every 6 hour regimen (i.e. 12.4 mcg/mL), withassociated peaks and troughs falling approximately within thetherapeutic antifibrinolytic range (5-15 mcg/mL; Cyklokapron NDA19-280). In certain embodiments, a two-compartment oral absorption andelimination simulation model coupled with pharmacokinetic data(Pilbrant, et al., Eur. J. Clin. Phannacol, (1981)-20:65-72), andmodified-release tablet dissolution performance information were used todetermine the preferred lead dosage regimen.

In immediate release formulations the entire dose and the solublecomponents in the dosage form dissolve in gastrointestinal fluid andpresent a high concentration of solutes for absorption. The mostfrequently reported adverse effects are primarily confined to theproximal gastrointestinal tract (nausea and vomiting). These adversesymptoms appear to be related to the drug load presented to the gastricmucosa, since this effect can be minimized by reducing theimmediate-release oral formulation dose or administering the productslowly by the intravenous route. In certain embodiments, a lowerincidence of proximal gastrointestinal adverse effects is obtained withthe preferred oral modified release formulation (e.g., dosed 1.3 g every8 hours) of the invention, e.g., because of the modified releaseproperties of the drug product formulation.

In certain embodiments, the oral dosage form of the present inventionprovides for an increased bioavailability as compared to immediaterelease oral dosage forms currently available (e.g., Cyclokapron). Incertain preferred embodiments the increased bioavailability allowstherapeutic plasma levels of tranexamic acid to be reached with a lowerdose of drug. Preferably, the increased bioavailability also decreasesthe amount of tranexamic acid that remains unabsorbed in thegastrointestinal which leads to decreased incidence of side effects thatare typically associated with formulations that provide higher levels ofunabsorbed tranexamic acid and prolonged exposure of thegastrointestinal tract to the higher tranexamic acid levels. Preferablythe oral dosage form of the present invention provides for abioavailability of tranexamic acid of greater than 40%, from about 41%to about 60%, preferably from about 42% to about 50%, more preferablyabout 45% after oral administration to humans.

The modified release oral formulations of tranexamic acid of the presentinvention provides a release of the drug which is slower than that ofthe immediate release 500 mg Cyklokapron product current marketed inCanada which provided a mean release rate of 100% by weight tranexamicacid released by about 15 minutes when measured utilizing USP 27Apparatus Type II paddle method @50 RPM in 900 ml water at 37-0.5° C.

In certain embodiments, the modified release oral formulations may bedescribed as providing a mean transit time through the proximalgastrointestinal mucosa which takes approximately one half hour longerthan an immediate release formulation. In other preferred embodiments,the modified release formulations of the invention provide a rate ofrelease of (dissolved) tranexamic acid from the dosage form in-vitrowhich is approximately 20, 40, 60, 80, and 100 percent of the total doseat 0.25, 0.5, 0.75, 1 and 1.5 hours, respectively. In certain preferredembodiments, such a release rate in-vitro demonstrates that theformulations of the present invention provide a relative reduction inthe amount and rate of dissolved tranexamic acid presented to theproximal gastric mucosa to approximate 20, 40, 60, 80, and 100 percentof the total dose at 0.25, 0.5, 0.75, 1 and 1.5 hours, respectively,after oral administration.

In certain embodiments, the majority of tranexamic acid absorptionappears to occur slowly distal to the stomach, and assuming linearpharmacokinetics, the modified release formulation produces anabsorption profile which is comparable to that achieved with thecurrently available oral immediate release formulations used outside theU.S.

In accordance with the present invention a modified release tranexamicacid tablet for oral administration is disclosed. Preferably, the tabletcontains at least one material (defined herein as any substance otherthan the active, i.e., tranexamic acid) which minimizes or eliminatesthe adverse gastrointestinal side effects in patients, for example,women dosed with oral tranexamic acid for treatment of menorrhagia.

The modified release oral dosage forms of tranexamic acid for purposesof the present invention include formulation ingredients and/orconfigurations which are typically utilized for formulations known inthe art as extended, sustained and controlled release formulations,although modified to provide a desirable release rate in keeping withthe teachings of the present invention. The modified releaseformulations preferably decrease the concentration of tranexamic acidand materials dissolved in the stomach fluids after dosing bycontrollably releasing tranexamic acid over a period of time, as opposedto immediate release formulations which release the entire dose oftranexamic acid all at once. The modified release formulations of thepresent invention thus minimize or prevent gastrointestinal reactionsand side effects that occur when a dose of tranexamic acid is ingestedand immediately reaches the stomach.

The modified release dosage forms of the present invention may beprepared as; tablets, capsules, granules, pellets, powders, dragees,troches, non-panels, pills or encapsulated suspension, and may bepackaged into capsules, sachets, etc. Such dosage forms may be preparedby any formulation technique where release of the active substance(tranexamic acid) from the dosage form is modified to occur at a slowerrate than from an immediate release product. In these formulations,tranexamic acid release occurs in the stomach and/or intestine, but at aslower rate so that a bolus of dissolved drug does not reach the liningof the stomach and cause adverse effects, or adverse effects occur witha lower intensity or frequency because of the lower concentration oftranexamic acid. Hence, adverse effects are preferably reduced,minimized or eliminated.

Methods of preparing modified release formulations are found in ModifiedRelease Drug Delivery Technology, Rathbone, Hadgraft, and Roberts, Eds.,Drugs and the Pharmaceutical Sciences, Vol. 126, Marcel Dekker Inc., NewYork, 2003; Modern Pharmaceutics, Third Edition, Banker and Rhodes, Eds.Drugs and the Pharmaceutical Sciences, Vol. 72, Marcel Dekker Inc., NewYork, 1996; Sustained and Controlled Release Drug Delivery Systems,Robinson, Ed., Drugs and the Pharmaceutical Sciences, Vol. 6, MarcelDekker Inc., NY 1978; Sustained Release Medications, Chemical TechnologyReview No. 177, Johnson, Ed., Noyes Data Corporation 1980; ControlledDrug Delivery, Fundamentals and Applications, Second Edition, Robinsonand Lee, Eds., Marcel Dekker Inc., New York, 1987, and as described inU.S. Pat. No. 6,548,084, each of these references being expresslyincorporated by reference herein in its entirety.

Preferably, a modified release form, makes tranexamic acid availableover an extended period of time after ingestion. Modified release dosageforms coupled with the digestion process and the absorption process inthe gastrointestinal tract cause a reduction in the amount of tranexamicacid in solution in the gastrointestinal tract compared to dosingtranexamic acid-presented as a conventional dosage form (e.g., as asolution, or as an immediate release dosage form). The modified releaseformulation may be verified by in vitro dissolution testing and in vivobioequivalence documentation, according to Food and Drug Administrationstandards, e.g., as set forth at www.fda.gov, 21 CFR §314, 320, and alsoat USP 23 NF 18 §711, 724. For example, an in vitro dissolution testsuch as USP 27 Apparatus Type II Paddle Method @50 RPM in 900 ml waterat 37-0.5° C. may be used to verify the release of the tranexamic acidfrom the dosage form.

Tranexamic acid modified release tablets may be formulated to provide adose of tranexamic acid, typically about 500 mg to about 2 grams fromone to two tablets, within about the first one to two hours after thetablet is ingested. Thus, tranexamic acid release occurs at a designedrate over a period e.g., about 60 minutes to about 120 minutes. The rateof tranexamic acid release over this period of time is designed toprovide a reduced concentration of tranexamic acid in the stomach whileallowing the absorption of tranexamic acid to occur throughout thegastrointestinal tract. Absorption of tranexamic acid typically beginsas soon as tranexamic acid is released from the dosage form and isdissolved in the gastrointestinal fluids contacting the membranes whichline the gastrointestinal tract. The rate of release of tranexamic acidfrom the dosage form and the absorption of drug by the gastrointestinalmucosa help to maintain low concentrations of drug in thegastrointestinal fluids. The lowered concentrations preferably result inlower intensity, frequency, and/or severity of gastrointestinal adverseside effects. The designed rate of release of tranexamic acid from thedosage form in the stomach and the upper small intestine, the naturalemptying of gastric juice containing any dissolved tranexamic acid fromthe stomach, and the absorption of tranexamic acid from a larger segmentof the gastrointestinal tract (i.e., both the stomach and the smallintestine, rather than the stomach only or the lower portion of thesmall intestine if any modified release dosage form with a longerrelease time was used), preferably results in reduced levels ofdissolved tranexamic acid in the region of the gastrointestinal tractproximal or distal to the dosage form. Reduced concentrations oftranexamic acid along the gastrointestinal tract preferably provide areduction in adverse gastrointestinal effects associated with oraltranexamic acid therapy.

As used herein, alleviation of adverse effects using these formulationsindicates any relief in one or more symptoms, such as decrease inincidence, severity, or duration of symptoms, and is not limited toabsence of symptoms or elimination of symptoms. Thus, treatment includesany decrease in incidence, duration, intensity, frequency, etc. ofadverse gastrointestinal symptoms including, but not limited to,headache, nausea, vomiting, diarrhea, constipation, cramping, bloating,and combinations thereof. The formulations may reduce symptoms at anytime during tranexamic acid therapy, but minimized adverse effects areparticularly noted immediately or shortly after dosing, that is, withinthe first few hours after dosing. As used herein, adversegastrointestinal effects and side effects are used interchangeably toindicate nontherapeutic effects (i.e., not relating to any possiblebeneficial effects due to tranexamic acid), ranging from unpleasant buttolerable sensations to severe gastrointestinal symptoms. As usedherein, the terms oral formulations, ingestable formulations, and orallyadministered formulations are used interchangeably and include anydosage forms which are ingested by mouth, including, but not limited to,tablets, pills, liquids, gelcaps, softgels, dragees, capsules, powders,granules, pellets, etc.

Modified release formulations of tranexamic acid include tablets,pellets, granules, capsules, or other oral dosage forms prepared in sucha way to release tranexamic acid in a designed manner. In certainembodiments, the modified release material is a gel-forming polymer, ahydratable polymer, a water soluble polymer, a water swellable polymer,or mixtures thereof.

In certain embodiments, modified release tranexamic acid tablets areprepared by adding a modified release material comprising a gel-formingor hydratable polymer to a tranexamic tablet composition. Suitablegel-forming or hydratable polymers include, but are not limited to,hydroxyproplycellulose, hydroxypropylmethylcellulose or hypromellose,carboxymethylcellulose, polyvinyl alcohol, etc. This provides acompressed tablet that may or may not be film coated. The tabletreleases tranexamic acid by diffusion of tranexamic acid through thetablet matrix, or by erosion of the tablet matrix, or by a combinationof diffusion from and erosion of the tablet matrix. Tablets formed withwater swellable polymers release tranexamic acid by diffusion oftranexamic acid through the tablet matrix, or by erosion of the tabletmatrix, or by a combination of diffusion from and erosion of the tabletmatrix. One or more water-soluble hydrophilic polymer(s) may also beused. These include polyvinylpyrrolidine, hydroxypropyl cellulose,hydroxypropylmethylcellulose, now referred to as hypromellose (e.g.,Methocel™, Dow Chemical Company), methyl cellulose, vinylacetate/crotonic acid copolymers, methacrylic acid copolymers, maleicanhydride/methyl vinyl ether copolymers, derivatives thereof andmixtures thereof. In various embodiments, the polymer is hydroxypropylcellulose or hydroxypropylmethylcellulose. The polymer may behydroxypropyl-methyl cellulose with a viscosity ranging from about 50cps to about 200 cps. The polymer may be hydroxypropyl-methyl cellulosewith a viscosity of 100 cps, commercially available as Methocel™ K 100LV (Dow Chemical Company). The amount of polymer in the composition maybe in the range of about 5% by weight to about 50% by weight of thecomposition. In various embodiments, the polymer is in the range ofabout 10% by weight to about 35% by weight of the composition, or about10% by weight to about 30% by weight of the composition.

In certain embodiments the modified release material comprises a vinylpolymer, phthalic acid derivative of vinyl copolymer,hydroxyalkylcellulose, alkylcellulose (e.g., ethylcellulose), celluloseacetate, hydroxyalkylcellulose acetate, cellulose ether, alkylcelluloseacetate and partial esters thereof, and polymers and copolymers of loweralkyl acrylic acids and lower alkyl acrylates and partial estersthereof, or combination thereof. In preferred embodiments the modifiedrelease material comprises hydroxypropylcellulose,hydryoxpropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol,polyvinylpyrrolidone, methylcellulose, vinyl acetate/crotonic acidcopolymers, methacrylic acid copolymers, maleic anhydride/methyl vinylether copolymers, derivatives thereof, and mixtures thereof. In furtherpreferred embodiments the modified release material comprises a polymersuch as a methacrylic acid copolymer. These are copolymers ofmethacrylic acid with neutral acrylate or methacrylate esters such asethyl acrylate or methyl methacrylate.

In certain embodiments the modified release material comprises a pHindependent binder or film-forming agent such as hydroxypropylmethycellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g., themethyl methacrylate/ethyl acrylate copolymers sold as Eudragit® (RohmPharma), starches, gelatin, sugars such as glucose, sucrose, andmannitol, silicic acid, carboxymethylcellulose, and the like, diluentssuch as lactose, mannitol, dry starch, microcrystalline cellulose andthe like, surface active agents such as polyoxyethylene sorbitan esters,sorbitan ethers, and the like, coloring agents, flavoring agents,lubricants such as talc, calcium stearate, and magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and other tableting aids.Any combination of the aforementioned binders or film-forming agents maybe included in the modified release material. The modified releasematerial may be combined with tranexamic acid to form modified releasedosage forms.

In certain embodiments, the formulation includes tranexamic acid in therange of about 50% by weight to about 95% or more by weight of theformulation. In other embodiments, tranexamic acid is in the range ofabout 60% by weight to about 90% by weight, or about 60% by weight toabout 80% by weight of the formulation. The remaining weight may be madeup of the modified release material and additional excipients.

To prepare modified release tablet formulations, the agent or modifiedrelease material to slow the release of tranexamic acid may beincorporated into the tablet matrix or coated onto the tablet surface orboth. In certain embodiments, tablet formulations prepared areformulated by granulating a blend of powders of the modified releasematerial. The powder blend is formed by combining portions of thepowdered components that make up the tablet. These powders areintimately mixed by dry-blending. The dry blended mixture is granulatedby wet mixing of a solution of a binding agent with the powder blend.The time for such wet mixing may be controlled to influence thedissolution rate of the formulation. For example, the total powder mixtime, that is, the time during which the powder is granulated, may rangefrom about 1 min to about 10 min, or from about 2 min to about 5 min.Following granulation, the particles are removed from the granulator andplaced in a fluid bed dryer, a vacuum dryer, a microwave dryer, or atray dryer for drying. Drying conditions are sufficient to removeunwanted granulating solvent, typically water, or to reduce the amountof granulating solvent to an acceptable level. Drying conditions in afluid bed dryer or tray dryer are typically about 50 to 70° C. Thegranulate is dried, screened, mixed with additional excipients such asdisintegrating agents, flow agents, or compression aids and lubricantssuch as talc, stearic acid, or magnesium stearate, and compressed intotablets.

In certain embodiments, the tablet that contains a modified releasematerial within the tablet matrix may be coated with an optionalfilm-forming agent. This applied film may aid in identification, mask anunpleasant taste, allow desired colors and surface appearance, provideenhanced elegance, aid in swallowing, aid in enteric coating, etc. Theamount of film-forming agent may be in the range of about 2% tabletweight to about 4% tablet weight. Suitable film-forming agents are knownto one skilled in the art and include hydroxypropyl cellulose, celluloseester, cellulose ether, one or more acrylic polymer(s), hydroxypropylmethylcellulose, cationic methacrylate copolymers (diethylaminoethyl)methacrylate/methyl-butyl-methacrylate copolymers such as Eudragit E®(Rohm Pharma) and the like. The film-forming agents may optionallycontain colorants, plasticizers, fillers, etc. including, but notlimited to, propylene glycol, sorbitan monooleate, sorbic acid, titaniumdioxide, and one or more pharmaceutically acceptable dye(s).

In certain embodiments, the tranexamic acid tablets of the invention arecoated with a modified release material. In certain embodiments,tranexamic acid tablets are formulated by dry blending, rotarycompacting, or wet granulating powders composed of tranexamic acid andtablet excipients. These powders are compressed into an immediaterelease tablet. Coating this immediate release tablet with a modifiedrelease material as described herein renders this tranexamic acid tabletas a modified release tablet.

In addition to the modified release material, the formulations of theinvention may also contain suitable quantities of other materials, e.g.preservatives, diluents (e.g., microcrystalline cellulose), lubricants(e.g., stearic acid, magnesium stearate, and the like), binders (e.g.,povidone, starch, and the like), disintegrants (e.g, croscarmellosesodium, corn starch, and the like), glidants (e.g., talc, colloidalsilicon dioxide, and the like), granulating aids, colorants, andflavorants that are conventional in the pharmaceutical art. Specificexamples of pharmaceutically acceptable excipients that may be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (2003),incorporated by reference herein.

The release process may be adjusted by varying the type, amount, and theratio of the ingredients to produce the desired dissolution profile, asknown to one skilled in the art. A coating may be a partiallyneutralized pH-dependent binder that controls the rate of tranexamicacid dissolution in aqueous media across the range of pH in the stomach,which has a pH of about 2, and the intestine, which has a pH of about5.5 in its upper region. In certain embodiments, one or more pHdependent binders may be used to modify the dissolution profile so thattranexamic acid is released slowly and continuously as the formulationpasses through the stomach and/or intestines.

In one embodiment, compressed modified release tablets are formulated tocomply with USP criteria and to be of such a size and shape to be easyto swallow. The size of the tablet will depend upon the dose oftranexamic acid that is needed to provide adequate therapy and theparticular formulation and excipients that are selected to provide thephysical properties necessary for tableting and for modified release. Invarious embodiments, a compressed modified release tablet contains fromabout 500 mg to about 1 gram of tranexamic acid, or from about 600 mg toabout 750 mg of tranexamic acid. The daily dose of tranexamic acid maybe achieved by taking one or two tablets at each dosing time.

In certain embodiments, the tranexamic acid included in the dosage formis from about 375 mg to about 1500 mg, preferably from about 375 mg toabout 1000 mg. In one embodiment, the dose of tranexamic acid per tabletis in the range of about 500 mg to about 1000 mg for tablets and fromabout 500 mg to about 1500 mg for a sachet filled with granules. Inanother embodiment, the dose of tranexamic acid is in the range of about3 grams/day to about 6 grams/day in three or four divided doses. As anexample, a total daily dose of 3 grams tranexamic acid may be dividedinto three doses of one tablet each with each tablet containing 1 gramtranexamic acid, or may be divided into four doses of one tablet eachwith each tablet containing 0.75 gram tranexamic acid. As anotherexample, a total daily dose of 4 gram tranexamic acid may be dividedinto three doses of two tablets at each dose with each tablet containing0.666 gram tranexamic acid, or may be divided into four doses of onetablet each with each tablet containing 1 gram tranexamic acid. Asanother example, a total daily dose of 5 gram tranexamic acid may bedivided into three doses of one tablet each with each tablet containing1.66 gram tranexamic acid, or may be divided into four doses of twotablets each with each tablet containing 0.625 gram tranexamic acid. Asanother example, a total daily dose of 6 gram tranexamic acid may bedivided into three doses of two tablets each with each tablet containing1 gram tranexamic acid, or may be divided into four doses of two tabletseach with each tablet containing 0.75 gram tranexamic acid. For ease ofswallowing, the dose of tranexamic acid taken at each dosing time may bedelivered by taking multiple tablets. For example, the 4 gram daily dosemay be delivered by taking two 666.67 mg tablets three times a day ortwo 500 mg tablets four times a day. Similarly, the 3 gram daily dosemay be achieved by taking two 550 mg tablets three times a day or two375 mg tablets four times a day. Alternatively, for ease of reference, adose of 600 mg, 650 mg, or 700 mg of tranexamic acid per tablet may beused. In a preferred embodiment, a total daily dose of 3900 mg/day isadministered in three divided doses of 1300 mg of two tablets at eachdose with each tablet containing 650 mg of tranexamic acid.Alternatively, each dose may be delivered by taking granules containingthe prescribed amount of tranexamic acid presented in a convenient unitdose package. Such examples are not limiting and other doses withinthese ranges will be appreciated by those skilled in the art.

Alternatively, modified release tranexamic acid formulations may beadministered by pellets or granules in e.g., a sachet or capsule.Modified release tranexamic acid pellets or granules may be prepared byusing materials to modify the release of tranexamic acid from thegranule or pellet matrix. Modified release preparations may also beformulated using coatings to modify the release of tranexamic acid fromthe granule or pellet. U.S. Pat. Nos. 5,650,174; and 5,229,135 each ofwhich is expressly incorporated by reference herein in its entirety,disclose variations on fabricating a pellet or nonpareil dosage form.Spheres are filled into packets, termed sachets, or capsules which arefilled by weight to contain the prescribed dose of drug.Multiparticulates may be coated with an modified release coating, asdisclosed in U.S. Pat. No. 6,066,339, which is expressly incorporated byreference herein its entirety. Coated multiparticulates may be packagedin capsules or sachets. The formulation of granules or pellets formodified release is described in Multiparticulate Oral Drug Delivery,Ghebre-Sellassie, Ed. in Drugs and the Pharmaceutical Sciences, Vol. 65Marcel Dekker Inc. NY, 1994 and in the relevant parts of the referencesfor modified release formulations previously cited and the relevantportions incorporated herein by reference.

In certain embodiments, the inventive tranexamic acid formulations maybe used for additional indications other than menorrhagia, such asconization of the cervix, epistaxis, hyphema, hereditary angioneuroticedema, a patient with a blood coagulation disorder undergoing dentalsurgery, combinations thereof, and the like.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will be further appreciated with respect to the followingnon-limiting examples. Other variations or embodiments of the inventionwill also be apparent to one of ordinary skill in the art from the abovedescriptions and examples. Thus, the forgoing embodiments are not to beconstrued as limiting the scope of this invention.

Example 1

Modified release 650 mg tranexamic acid tablets were prepared having theingredients listed in the Table 1 below:

TABLE 1 Quantity Quantity per batch per tablet Ingredient (kg) (mg)Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive IngredientsMicrocrystalline Cellulose NF (Avicel PH 101) 5.753 44.25 ColloidalSilicon Dioxide NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Hypromellose, USP (Methocel K3 Premium LV) 19.110 147.00 Povidone,USP (K value range 29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.34018.00 Magnesium Stearate, NF (powder) 0.585 4.50 Purified Water USP*17.550 135.00 *Purified water is removed during processingThe formulation of Example 1 was prepared as follows:1. Weigh all ingredients and keep in moisture resistant containers untilready for use.2. Measure water into a container. Mix povidone at medium speed untilcompletely dissolved.3. Add tranexamic acid, microcrystalline cellulose (MCC), pregelatinizedcorn starch, and colloidal silicon dioxide to the high shear mixer.4. Mix using impeller only.5. Mix for an additional time (impeller only). Add all of the povidonesolution during this mixing step.6. Mix until adequately granulated (impeller and chopper). Proceed onlywhen desired granulation has been achieved. Add additional water ifnecessary.7. Dry the granulation to moisture content of NMT 1.2%.8. Pass the granulation through the oscillating granulator equipped witha #30 mesh screen. Weigh the granulation. Add granulation to theV-Blender.9. Add the hypromellose USP Methocel K3 Premium to the V-blender. Blend.10. Pass magnesium stearate and stearic acid through oscillatinggranulator equipped with a #40 mesh screen. Add magnesium stearate andstearic acid to the V-blender and blend.11. Perform specified physical property testing. Proceed to compression.12. Compress tablets to desired weight.

Example 2

In Example 2, immediate release 650 mg tranexamic acid tablets wereprepared having the ingredients listed in Table 2 below:

TABLE 2 Quantity per Quanity per batch tablet Ingredient (kg) (mg)Active ingredient Tranexamic Acid, EP (650 mg/tab) 84.50 650.0 Inactiveingredients Microcrystalline Cellulose, NF 5.753 44.25 (Avicel PH 101)Microcrystalline Cellulose, NF 10.660 82.00 (Avicel PH 102) ColloidalSilicon Dioxide, NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Croscarmellose Sodium, NF 19.50 15.00 Povidone, USP (K value range29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.340 18.00 MagnesiumStearate, NF (powder) 0.585 4.50 Purified Water, USP* 17.550 135.00 FilmCoating (Inactive Ingredients)** Opadry White YS-1-7003 4.110 — PurifiedWater, USP 36.990 — *Purified water is removed during processing **6 kgexcess prepared to account for losses during transferThe formulation of Example 2 was prepared as follows:1. Weigh all ingredients and keep in moisture resistant containers untilready for use.2. Measure water into a container. Mix povidone at medium speed untilcompletely dissolved.3. Add tranexamic acid, microcrystalline cellulose (MCC), pregelatinizedcorn starch, and colloidal silicon dioxide to the high shear mixer.4. Mix using impeller only.5. Mix for an additional time (impeller only). Add all of the povidonesolution during this mixing step.6. Mix until adequately granulated (impeller and chopper). Proceed onlywhen desired granulation has been achieved. Add additional water ifnecessary.7. Dry the granulation to moisture content of NMT 1.2%.8. Pass the granulation through the oscillating granulator equipped witha #30 mesh screen. Weigh the granulation. Add granulation to theV-Blender.9. Add the croscarmellose sodium and MCC to the V-Blender and blend.10. Pass magnesium stearate and stearic acid through oscillatinggranulator equipped with a #40 mesh screen. Add magnesium stearate andstearic acid to the V-blender and blend.11. Perform specified physical property testing. Proceed to compression.12. Compress tablets.12. After compression, spray coat the compressed dosage forms with theOpadry White in water.

Example 3

In Example 3, modified release 650 mg tranexamic acid tablets wereprepared as in Example 1 and coated with a film coating similar to theimmediate release tablets of Example 2. The ingredients are listed inTable 3 below:

TABLE 3 Quantity Quantity per batch per tablet Ingredient (kg) (mg)Active Ingredient Tranexamic Acid, EP 84.50 650.0 Inactive IngredientsMicrocrystalline Cellulose NP (Avicel PH 101) 5.753 44.25 ColloidalSilicon Dioxide NF 0.0975 0.75 Pregelatinized Corn Starch, NF 6.43549.50 Hypromellose, USP (Methocel K3 Premium LV) 19.110 147.00 Povidone,USP (K value range 29-32) 4.680 36.00 Stearic Acid, NF (powder) 2.34018.00 Magnesium Stearate, NF (powder) 0.585 4.50 Purified Water USP*17.550 135.00 Film Coating (Inactive Ingredients)** Opadry WhiteYS-1-7003 4.305 Purified Water, USP 38.750 *Purified water is removedduring processing **6 kg excess prepared to account for losses duringtransfer

Example 4 Bioavailability and Bioequivalence Evaluation

In Example 4, a comparative, randomized, single dose, 4-way CrossoverAbsolute Bioavailability (BA) and Bioequivalence (BE) study ofTranexamic Acid Tablet Formulations prepared in accordance with Examples1 and 2 in Healthy Adult Women Volunteers under Fasting Conditions wasperformed. The objective was to assess the bioequivalence of a 650 mgmodified release tablet formulation prepared in accordance with Example1 compared to the immediate release reference tablet formulation oftranexamic acid prepared in accordance with Example 2, and to determinethe bioavailability of the modified tablet formulation to the approvedIV (1 g) formulation Cyklokapron® by Pharmacia & Upjohn. The design wasa randomized, 4-way crossover, comparative BE and BA determination. Alloral doses administered were 1.3 g. Twenty-eight (28) healthynon-smoking adult female volunteer subjects were enrolled in the study.Sample size was calculated assuming a 25% CV in AUC_(inf). The studyendpoints were the 90% confidence intervals of the ratio ofleast-squares means of the pharmacokinetic parameters AUC_(0-t),AUC_(inf) and C_(max) of the modified release formulation to theimmediate-release formulation from serum concentration-time data drawnup to 36 hours after a single dose of drug. In addition, thebioavailability of the tablet formulations were calculated. Smokers,oral contraceptive users, those with a previous history ofthromboembolic events and altered vision were excluded from the study.ECG monitoring was performed before, during and after the estimatedtimes of peak serum tranexamic acid concentrations exposure. Adverseevents were captured and recorded throughout the trial period.

In the study, subjects were randomized to receive single oral 1.3 g(2×650 mg tablets) dose of tranexamic acid in tablet forms whichincluded a modified release dosage form and an immediate release dosageform. Subjects were also administered a single 1 g (10 ml) IV solutionof tranexamic acid (100 mg/ml concentration).

A summary of the pharmacokinetic results from the study of Example 4 arelisted in the tables below.

TABLE 4 Summary of Results-Tranexamic Acid in Plasma PharmacokineticParameters (N = 26) ln AUC 0-t* ln AUCinf* ln Cmax* (mcg · h/mL, (mcg ·h/mL) (mcg/mL) Modified Release formulation Mean 66.703 69.642 11.251088CV 26.8 27.2 29.1 N 26 24 26 Immediate Release formulation Mean 70.15772.656 12.260414 CV 16.2 16.4 23.0 N 26 24 26 Least-Squares Mean:Modified Release 66.935 68.891 11.321919 Immediate Release 70.051 72.41112.258222 Ratio of 95.6 95.1 92.4 Least-Squares Mean (modifiedrelease/immediate release) % *For ln-transformed parameters, the analogof the mean (i.e. the geometric mean) is reported. AUCinf, kel,half-life and F could not be estimated for some subjects. AUC 0-t is thearea under the plasma concentration versus time curve, from time 0 tothe last measurable concentration, as calculated by the lineartrapezoidal method.

TABLE 5 Summary of Results-Tranexamic Acid in Plasma PharmacokineticParameters (N = 26) Tmax Half-life kel F (h) (h) (1/h) (%) ModifiedRelease formulation Mean 2.942 11.370 0.06300 44.93 CV 22.7 17.6 19.425.3 n 26 26 26 24 Immediate Release formulation Mean 2.808 11.0130.06438 46.04 CV 20.8 15.5 15.3 16.1 n 26 24 24 24

TABLE 6 Summary of Results-Tranexamic Acid in Plasma PharmacokineticParameters (N = 26) Ln AUC 0-t* ln AUCinf* ln Cmax* (mcg · h/mL) (mcg ·h/mL) (mcg/mL) 90 % Confidence Intervals (Modified release/Immediaterelease) % lower limit: 87.8% 87.4% 84.0% upper limit: 104.0% 103.5%101.6% p-Value (ANOVA) Modified vs Immediate 0.3721 0.3259 0.1676 Period0.0704 0.0499 0.0356 Sequence 0.7734 0.7978 0.8207 Intrasubject CV %18.3 17.4 20.6 *For ln-transformed parameters, the antilog of the mean(i.e. the geometric mean) is reported. AUCinf, kel, half-life and Fcould not be estimated for some subjects.

Concentration-time profiles for the study of Example 4 are presented onsemi-log and linear scale over 36 hours and are depicted in FIGS. 3 and4.

The following pharmacokinetic parameters in the table below werecalculated for tranexamic acid in plasma for the study of Example 4.

-   -   MRT: The mean residence time (MRT) after intravenous        administration of tranexamic acid was determined using the        equation, AUMC/AUC+infusion time/2, where the AUMC is the area        under the moment-time curve.    -   MTT: Following oral administration of the Modified Release and        Immediate Release formulations, the mean transit time (MTT) of        tranexamic acid was calculated by dividing the AUMC by the AUC.    -   MAT: The mean abso rption time (MAT) for the two formulations        was derived by subtracting the MRT from the MTT.        Mean (±SD) results are presented in the table below:

TABLE 7 IV Modified Release Immediate Release MRT (hours) 3.51 ± 0.38N/A N/A MTT (hours) N/A 7.70 ± 0.72 7.21 ± 1.01 MAT (hours) N/A 4.18 ±0.70 3.70 ± 0.94

The mean transit time (MTT) and mean absorption time (MAT) of theModified Release formulation of tranexamic acid was approximately 30minutes longer than that observed for the Immediate Release formulation.

The most frequently reported adverse events from the study of Example 4are listed in the table below. The table lists the number of subjectsreporting adverse events, and the percentage of subjects is inparentheses.

TABLE 8 Treatment Modified Immediate IV solution Release Release (10 ×(2 × 650 mg) (2 × 650 mg) 100 mg/ml) Adverse Events (n = 27) (n = 27) (n= 27) Headache  4 (15%)  7 (26%)  7 (26%) Nausea 0 (0%) 2 (7%) 10 (37%)Dizziness 0 (0%) 0 (0%) 11 (41%) Feeling Hot 0 (0%) 0 (0%)  6 (22%)Nasal Congestion 2 (7%) 1 (4%) 1 (4%) Cough 0 (0%) 0 (0%) 2 (7%) Urineodor abnormal 2 (7%) 0 (0%) 1 (4%)

Dissolution Results for Immediate Release and Modified ReleaseFormulations prepared in accordance with Examples 2 and 1 respectivelyused in the study of Example 4 tested under USP 27 Apparatus Type IIPaddle Method @50 RPM in 900 ml water at 37±0.5° C. are listed in thetables below.

TABLE 9 Test Results for the Immediate Release Formulation in Table 2.Assay %  99.9% Content Uniformity  99.4% RSD   0.7% Unknown Related NMT0.2% Each <0.1% Substance Total Related Substances NMT 2.0% Total <0.1%and Impurities Dissolution Profile 15 min.  58.0% 30 min.  96.0% 45 min.102.0% 60 min. 104.0%

TABLE 10 Test Results for the Modified Release Formulation in Table 1Assay % 99.4% RSD Content Uniformity 98.5%   0.6% Unknown Related NMT0.2% Each <0.1% Substance Total Related Substances NMT 2.0% Total <0.1%and Impurities Dissolution Profile 15 min. 21.0% 30 min. 40.0% 45 min.58.0% 60 min. 73.0% 90 min. 98.0%

Conclusions:

The ratios of least-squares means and the 90% confidence intervalsderived from the analyses of the ln-transformed pharmacokineticparameters AUC_(0-t), AUC_(inf) and C_(max) for tranexamic acid inplasma were within the 80-125% Food and Drug Administration (FDA)acceptance range for the modified release formulation versus theimmediate release formulation under fasting conditions.

The absolute bioavailability of the modified release and immediaterelease tablet formulations were 44.93% and 46.04% respectively.

Based on these results, the modified release tranexamic acid tabletformulation and the immediate release tranexamic acid formulation arebioequivalent under fasting conditions.

Example 4A Comparative Example

In Comparative Example 4A, a 500 mg immediate release tranexamic acidtablet, approved and marketed in Canada under the name Cyklokapron wasobtained and dissolution tested under USP 27 Apparatus Type II PaddleMethod @50 RPM in 900 ml water at 37±0.5° C. The dissolution results arelisted in Table 10A below:

TABLE 10A % dissolved % dissolved % dissolve % dissolved Sample # in 15min. in 30 min. in 45 min. in 60 min. 1 102 104 105 106 2 102 104 105106 3 101 102 102 105 4 99 101 102 103 5 100 102 103 104 6 99 101 102104 Average 101 102 103 105 % RSD 1.4 1.3 1.4 1.1

Example 5

In Example 5, based on single dose pharmacokinetic parameters,pharmacokinetic simulations of serum concentrations were performed tocompare dosing the modified release formulation of Example 4 at every 8hours (Q8H: at 6:00 AM, 2:00 PM, 10:00 PM) and dosing three times a day,other than every 8 hours (TID: at 8:00 AM, 2:00 PM, and 10:00 PM). Theresults are provided in Tables 11-14 below.

TABLE 11 Tranexamic Acid - Modified Release Formulation Dosage RegimenSimulation - ORAL 1.3 g q8 hr Time (h) Dose (mcg) Conc. (mcg/mL) 01.30E+06 0 1 0 4.0594 2 0 10.0551 3 0 10.6433 4 0 9.20306 5 0 7.26932 60 5.4699 8 1.30E+06 2.89909 9 0 6.15391 10 0 11.5813 11 0 11.7752 12 010.0646 13 0 7.94622 14 0 6.02067 15 0 4.4712 16 1.30E+06 3.30248 17 06.51406 18 0 11.9097 19 0 12.0794 20 0 10.3495 21 0 8.21523 22 0 6.276123 0 4.71463 24 1.30E+06 3.53505 25 0 6.73663 26 0 12.1229 27 0 12.283828 0 10.5455 29 0 8.40336 30 0 6.45664 31 0 4.88791 32 1.30E+06 3.7013833 0 6.89628 34 0 12.2762 35 0 12.4309 36 0 10.6868 37 0 8.53894 38 06.5868 39 0 5.01286 40 1.30E+06 38.82133 41 0 7.01144 42 0 12.3867 43 012.537 44 0 10.7887 45 0 8.63675 46 0 6.68069 47 0 5.103 49 1.30E+063.90786 49 0 7.09451 50 0 12.4665 51 0 12.6136 52 0 10.8621 53 0 8.7073154 0 6.74842 55 0 5.16802 56 1.30E+06 3.97028 57 0 7.15443 58 0 12.52459 0 12.6688 60 0 10.9152 61 0 8.7582 62 0 6.79728 63 0 5.21493 641.30E+06 4.01531 65 0 7.19766 66 0 12.5655 67 0 12.7087 68 0 10.9534 690 8.79492 70 0 6.83253 71 0 5.24877 72 1.30E+06 4.0478 73 0 7.22885 74 012.5954 75 0 12.7374 76 0 10.981 77 0 8.82141 78 0 6.85796 79 0 5.2731880 1.30E+06 4.07124 81 0 7.25135 82 0 12.617 83 0 12.7581 84 0 11.000985 0 8.84052 86 0 6.87631 87 0 5.29079 88 1.30E+06 4.08814 89 0 7.2675890 0 12.6326 91 0 12.7731 92 0 11.0153 93 0 8.8543 94 0 6.88954 95 05.3035 96 1.30E+06 4.10034 97 0 7.27929 98 0 12.6439 99 0 12.7839 100 011.0256 101 0 8.86425 102 0 6.89909 103 0 5.31266 104 1.30E+06 4.10913105 0 7.28773 106 0 12.652 107 0 12.7917 108 0 11.0331 109 0 8.87142 1100 6.90597 111 0 5.31927 112 1.03E+06 4.11548 113 0 7.29382 114 0 12.6578115 0 12.7973 116 0 11.0385 117 0 8.8766 118 0 6.91094 119 0 5.32404 1200 4.12006

Concentration-time profiles are presented over 120 hours for themodified release formulation in Table 12 and are depicted in FIG. 1. A 1g formulation administered q8h is also depicted for comparison purposes.

TABLE 12 Cmax, Cmin and Cavg for 1.3 g q8 hr simulation Simulation at120 hours Pharmacokinetic Parameter Concentration Cmax 12.8 mcg/mL Cmin 4.1 mcg/mL Cavg  8.4 mcg/ml

TABLE 13 Tranexamic Acid - Modified Release Formulation Dosage RegimenSimulation - ORAL 13 g TID (8:00 AM, 2:00 PM, and 10:00 PM) Time (h)Dose (mcg) Conc. (mcg/mL) 0 1.30E+06 0 1 0 4.0594 2 0 10.0551 3 010.6433 4 0 9.20306 5 0 7.26932 6 1.30E+06 5.4699 8 0 12.9542 9 012.7378 10 0 10.7293 11 0 8.40129 12 1.30E+06 6.33141 13 0 8.74352 14 013.505 15 0 13.2018 16 0 11.1327 17 0 8.76144 18 0 6.65976 19 0 4.9882320 0 3.73474 21 0 2.8275 22 0 2.18502 23 0 1.73555 24 1.30E+06 1.4224325 0 5.26298 26 0 11.104 27 0 11.5807 28 0 10.058 29 0 8.06103 301.30E+06 6.21137 31 0 8.76659 32 0 13.6187 33 0 13.3709 34 0 11.334 35 08.97998 36 1.30E+06 6.88576 37 0 9.27495 38 0 14.0147 39 0 13.6908 40 011.6019 41 0 9.21185 42 0 7.09208 43 0 5.40321 44 0 4.1331 45 0 3.2099146 0 2.55212 47 0 2.08796 48 1.30E+06 1.76074 49 0 5.58776 50 0 11.415851 0 11.88 52 0 10.3453 53 0 8.33688 54 1.30E+06 6.47618 55 0 9.02081 560 13.8627 57 0 13.6052 58 0 11.5589 59 0 9.1959 60 1.30E+06 7.09304 61 09.47395 62 0 14.2057 63 0 13.8742 64 0 11.778 65 0 9.38036 66 0 7.2543367 0 5.55898 68 0 4.28264 69 0 3.35346 70 0 2.68993 71 0 2.22026 721.30E+06 1.88775 73 0 5.70968 74 0 11.5329 75 0 11.9924 76 0 10.4532 770 8.44044 78 1.30E+06 6.57559 79 0 9.11625 80 0 13.9543 81 0 13.6931 820 11.6434 83 0 9.27696 84 1.30E+06 7.17086 85 0 9.54865 86 0 14.2775 870 13.943 88 0 11.8441 89 0 9.44431 90 0 7.31525 91 0 5.61745 92 04.33877 93 0 3.40735 94 0 2.74167 95 0 2.26992 96 1.30E+06 1.93543 97 05.75546 98 0 11.5768 99 0 12.0346 100 0 10.4937 101 0 8.47931 1021.30E+06 6.61292 103 0 9.15208 104 0 13.9887 105 0 13.7261 106 0 11.6751107 0 9.30739 108 1.30E+06 7.20008 109 0 9.5767 110 0 14.3044 111 013.9689 112 0 11.8689 113 0 9.46813 114 0 7.33811 115 0 5.63941 116 04.35985 117 0 3.42759 118 0 2.76109 119 0 2.28857 120 0 1.95333

Concentration-time profiles are presented over 120 hours for themodified release formulation in Table 14 and are depicted in FIG. 2. A 1g formulation administered TID is also depicted for comparison purposes.

TABLE 14 Cmax, Cmin and Cavg for 1.3 g TID (8:00 AM, 2:00 PM, and 10:00PM) Simulation at 120 hours Pharmacokinetic Parameter Conc. Cmax 12.0,14.0, 14.3 mcg/mL Cmin 1.9, 6.6, 7.2 mcg/mL Cavg 8.4 mcg/mL

Example 6

In Example 6, a study of a single dose followed by multiple doses, wasperformed on 20 healthy non-smoking adult female volunteers using amodified release formulation prepared in accordance with Example 1.After an overnight fast, subjects received a single oral dose oftranexamic acid (1.3 g) on Day 1. Blood samples were taken before dosingand up to 36 hours post-dose. Subjects received another single oral doseof tranexamic acid (1.3 g) on the evening of Day 2, and 3 times a day(every 8 hours) starting on the morning of Day 3 until the last dose onthe morning of Day 7. Blood samples were taken before the 6th, 9th, 12thand 15th dose (the last dose) for the determination of C_(min), and upto 8 hours after the last dose, for the determination of drugconcentration at steady-state. Subjects were housed from at least 10hours before the 1st dose on Day 1 until after the 8-hour blood drawfollowing the 15th dose (on Day 7).

Tranexamic acid is minimally bound (approximately 3%) to plasma proteins(mainly plasminogen) at “typical” therapeutic plasma concentrations ofapproximately 5-15 mg/L. The main route of elimination of tranexamicacid is renal glomerular filtration. After oral administration oftranexamic acid (250 or 500 mg) to healthy adults, between 40-70% of theadministered dose is excreted unchanged in the urine within 24 hours.After IV administration (1 g) 30% of the dose is excreted unchanged inthe urine within one hour, 45-55% within 2-3 hours and 90% within 24hours.

The beta elimination half-life of tranexamic acid is 2 hours. Based onpublished data, the mean C_(max) and AUC₀₋₆ pharmacokinetic parametersafter a single 1.3 g oral dose of tranexamic acid are expected to beapproximately 65% of those achieved with a 2 g dose (i.e. ˜10 mg/L and˜40 mg-h/L, C_(max) and AUC₀₋₆ under fasting conditions, respectively).

However, the pharmacokinetics of tranexamic acid were not adequatelycharacterized in Pilbrant, et al., Eur. J. Clin. Pharmacol.(1981)-20:65-72, since blood samples were collected for up to only 6hours post-dose. In addition, the plasma concentration-time curves afterIV administration showed three exponential phases, with a gammaelimination half-life of approximately 7 hours. For this reason, theconcentration-time profile of tranexamic acid was estimated bysimulating the data over 36 hours, after oral administration of a 1.3 gdose under fasting conditions, using NONMEM. Based on the simulationresults, it would be appropriate to collect blood samples until 36 hoursin order to characterize the AUC, Cmax, tmax, t½ and F.

The objective of this study of Example 6 was to assess thepharmacokinetic linearity of the test tablet formulation of tranexamicacid (modified release), after a single oral dose (Day 1) compared to adaily (1.3 g every 8 hours) dosage regimen (Days 2 to 7), under fastingconditions.

In the study of Example 6, blood samples (1×5 mL) were collected inblood collection tubes containing lithium heparin at Hour 0 (pre-dose)on Day 1, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14, 24,28, 32, and 36 hours post-dose. Blood samples for Cmin determinationswere also collected immediately before the 6th, 9th, 12th, and 15thdoses on Days 4, 5, 6, and 7, respectively, and at the following timesafter the 15th dose: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours.Plasma samples were separated by centrifugation, then frozen at −20°C.±10° C. and kept frozen until assayed at AAI Development Services inNew-Ulm, Germany.

Noncompartmental Pharmacokinetic Parameters

Calculations for plasma tranexamic acid were calculated bynoncompartmental methods using the following pharmacokinetic parametersin Tables 15 and 16:

Day 1:

TABLE 15 AUC 0-t: The area under the plasma concentration versus timecurve, from time 0 to the last measurable concentration, as calculatedby the linear trapezoidal method. AUCinf: The area under the plasmaconcentration versus time curve from time 0 to infinity. AUCinf wascalculated as the sum of AUC 0-t plus the ratio of the last measurableplasma concentration to the elimination rate constant. AUC/AUCinf: Theratio of AUC 0-t to AUCinf. Cmax: Maximum measured plasma concentrationover the time span specified. tmax: Time of the maximum measured plasmaconcentration. If the maximum value occured at more than one time point,tmax was defined as the first time point with this value. kel: Apparentfirst-order terminal elimination rate constant calculated from asemi-log plot of the plasma concentration versus time curve. Thisparameter was calculated by linear least squares regression analysisusing the maximum number of points in the terminal log-linear phase(e.g. three or more non-zero plasma concentrations). t½: Thee apparentfirst-order terminal elimination half-life was calculated as 0.693/kel.

No value for kel, AUCinf or t½ were reported for cases that did notexhibit a terminal log-linear phase in the concentration versus timeprofile.

Day 7:

TABLE 16 AUCτ: The area under the plasma concentration versus time curveover the final dosing interval, as calculated by the linear trapezoidalmethod. Cmax: Maximum measured plasma concentration over the finaldosing interval. Cmin: Measured plasma concentration prior to themorning dose. tmax: Time of the maximum measured plasma concentrationover the final dosing interval. If the maximum value occured at morethan one time point, tmax was defined as the first time point with thisvalue. Flux: Percent fluctuation was calculated as follows:${Flux}\mspace{14mu} 1\text{:}\mspace{14mu} \frac{{Cmax} - {Cmin}}{Cssav} \times 100$where Cssav was calculated as the ratio of AUC 0-τ to the dosinginterval, τ.${Flux}\mspace{14mu} 2\text{:}\mspace{14mu} \frac{{Cmax} - {Cmin}}{Cmin} \times 100$

Compartmental Pharmacokinetic Parameters

Compartmental analysis was performed on tranexamic acid data followingsingle and multiple oral administrations of the modified release (MR)tablet formulation. Multiple compartmental models were constructed andtheir ability to fit plasma concentrations of tranexamic acid wereevaluated using a standard two-stage (STS) approach with ADAPT-II(maximum likelihood analysis). The discrimination process was performedby computing the Akaike Information Criterion Test (AIC), the minimumvalue of the objective function (OBJ) and by looking at pertinentgraphical representations of goodness of fit (e.g. fitted and observedconcentrations versus time).

The final analysis was performed using an iterative two-stage approachwith the IT2S® software. This software uses a population methodologywhich allows one to provide robust PK parameter estimates on anindividual subject and population basis. All relevant pharmacokineticparameters were calculated and reported. Concentrations were modeledusing a weighting procedure of W_(j)=1/S_(j) ² where the variance σj²was calculated for each observation using the equation σj²(a+b*Y_(j))²where a and b are the intercept and slope of each variance model. Theslope is the residual variability associated with each concentration(includes the intra-individual variability and the sum of allexperimental errors), and the intercept is related to the limit ofdetection of the analytical assay. All PK parameter estimates wereupdated iteratively during the population PK analysis (VARUP, IT2S®)until stable values were found. The analysis included the quantitativeestimation of population PK parameters and interindividual variabilityof tranexamic acid in plasma.

Individual profiles of observed vs fitted plasma concentrations oftranexamic acid were provided for the MR formulation.

Statistical Analyses Descriptive Statistics

Descriptive statistics including arithmetic means, standard deviationsand coefficients of variation were calculated on the individualconcentration and pharmacokinetic data. Additionally, geometric meanswere calculated for the parameters AUC_(0-t), AUC_(inf), and C_(max) forDay 1 and AUCτ, C_(max) and C_(min) for Day 7.

Time Dependence Pharmacokinetic Linearity

The pharmacokinetic parameter AUCτ (Day 7) was compared againstAUC_(inf) (Day 1) using an analysis of variance (ANOVA) on theln-transformed values for tranexamic acid. The ANOVA model includedGroup, Day (1 (AUC_(inf)) and 7 (AUCτ)) and the interaction Day*Group asfixed effects. All the interaction terms were not statisticallysignificant, at a level of 5%, and were dropped from the final model.The ANOVA included calculation of least-squares means (LSM), thedifference between Day LSM and the standard error associated with thisdifference. The above statistical analysis was done using the SAS® GLMprocedure.

The ratio of LSM was calculated using the exponentiation of the Day LSMfrom the analysis on the ln-transformed response. The ratio wasexpressed as a percentage relative to AUC_(inf) (Day 1).

A ninety percent confidence interval for the ratio was derived byexponentiation of the confidence interval obtained for the differencebetween Day LSM resulting from the analysis on the ln-transformedresponse. The confidence interval was expressed as a percentage relativeto AUC_(inf) (Day 1).

Steady-State Analysis

A steady-state analysis was performed, on the ln-transformed pre-doseCmin concentrations at −72, −48, −24 and 0-hour time points, usingHelmert's contrasts. The ANOVA model included Group, Time and theinteraction Time*Group as fixed effects. In order to model thecorrelations within every subject, an appropriate variance-covariancematrix was chosen among the following: unstructured (UN), compoundsymmetry (CS), compound symmetry heterogeneous (CSH), variance component(VC), autoregressive (AR(1)), autoregressive heterogeneous (ARH(1)) andautoregressive moving average (ARMA(1,1)), using the Akaike's Burnhamand Anderson criterion (AICC). All the interaction terms were notstatistically significant, at a level of 5%, and were dropped from thefinal model. The ANOVA included also calculation of least-squares means(LSM) for each pre-dose C_(min) concentrations. Helmert's contrasts wereconstructed such that each time point is compared to the mean ofsubsequent time points. There are 3 contrasts associated to the 4pre-dose concentration timepoints. They are listed in Table 17 below:

TABLE 17 Contrast Tests Compar.1 Predose Day 4 compared to (mean predoseof Day 5, 6 and 7) Compar.2 Predose Day 5 compared to (mean predose ofDay 6 and 7) Compar.3 Predose Day 6 compared to predose Day 7 (0-hour)

The above statistical analyses were done using the SAS® Mixed procedure.

Formulae

The following formulae in Table 18 were used for the ratio ofleast-squares means and 90% confidence interval calculations derivedfrom the ANOVA on the ln transformed pharmacokinetic parameters.

TABLE 18 Ratio of Least- _(100×e) (LSM_(Day7) − LSM_(Day1)) squaresMeans: 90% _(100×e) (LSM_(Day7) − LSM_(Day1) ± t_(df.005) ×SE_(Day7−Day1)) Confidence Interval: Note: LSM_(Day7) and LSM_(Day1) arethe least-squares means of Day 7 and Day 1, as computed by the LSMEANSstatement of the SAS ® GLM procedure. t_(df,α) is the value of theStudent's t distribution with df degrees of freedom (i.e. degrees offreedom for the error term from the analysis of variance) and aright-tail fractional area of α (α = 0.05). SE_(Day7−Day1) is thestandard error of the difference between the adjusted Day means, ascomputed by the ESTIMATE statement in the SAS ® GLM procedure.

Discussion of Pharmacokinetic Results Time Dependence PharmacokineticLinearity

The ANOVA model included Group, Day (1 (AUC_(inf)) and 7 (AUCτ)) and theinteraction Day*Group as the fixed effect. All the interaction termswere not statistically significant, at a level of 5%, and were droppedfrom the final model. Pharmacokinetic linearity was calculated for theformulation using the same approach as above, but the ANOVA modelincluded Group, Day 1 (AUCinf) and Day 7 (AUCτ)) and the interactionsGroup*Day as fixed effects and Subject nested within Group as a randomeffect.

The pharmacokinetic linearity results are summarized in the table below.

TABLE 19 90% Confidence Interval Formulation Ratio AUCτ/AUCinf LowerLimit Upper Limit MR 97.3 86.5 109.5

The pharmacokinetic linearity results indicate that the ratios ofleast-squares means of AUCτ (Day 7) to AUC_(inf) (Day 1) and the 90%confidence interval for the MR formulation were within the 80-125%acceptance range. Based on these results, the 650 mg tranexamic acidmodified release tablets exhibited linear pharmacokinetics followingrepeated administration (7 days) of a 1.3 g dose under fastingconditions.

Steady-State Analysis

For the steady-state analysis, the CS variance-covariance matrix waschosen to model the correlations within every subject. Overall, theinteraction term (i.e. Time*Group) was not statistically significant andwas removed from the final ANOVA model. For each formulation, the sameapproach as above was used, but the ANOVA models included Group, Timeand the interactions Time*Group as fixed effects.

A summary of LSM results for the steady-state analysis are summarized inTable 20A below.

TABLE 20A Times Formulation Days (hour) LSM derived from the ANOVA MR 4−72 4.90536 5 −48 4.77323 6 −24 5.23678 7 0 5.15389

Summary of statistical comparisons for the steady-state analysis aresummarized in Table 20B below

TABLE 20B Formulation Helmert's contrasts P-value MR Predose Day 4compared to 0.4438 (mean predose of Day 5, 6 and 7) Predose Day 5compared to 0.0393 (mean predose of Day 6 and 7) Predose Day 6 comparedto predose Day 7 0.7318

Based on the results above, steady-state plasma concentration oftranexamic acid were reached on Day 4 (−72-hour), since the p value forthe first contrast was not statistically significant at a 5% alphaerror. It should be noted that the second comparison [Predose Day 5compared to (mean of Day 6 and 7)] was found to be statisticallysignificant.

The largest difference observed in predose plasma concentrations oftranexamic acid between the LSM of predose Day 5 compared to Day 6 and 7was less than 10%, which is not considered clinically relevant.Moreover, the last contrast was not statistically significant and theobserved difference between the LSM of predose Day 6 and 7 was less than2%.

Compartmental Pharmacokinetic Analysis

The mean apparent oral clearance (CUF) of the MR formulation calculatedwith compartmental methods was 17.7 L/h (295 mL/min). Based on previousdata reported in the literature, the group of Pilbrant, et al., havedetermined that the urinary recovery of tranexamic acid exceeded 95% ofthe dose administered. Considering the bioavailability of the MRformulation (Mean F: 44.9%, See Table 5), the systemic clearance (CL) oftranexamic acid (295 mL/min×0.449=123 mL/min) would be close to theglomerular filtration rate in healthy subjects (125 mL/min)5.

Using compartmental methods, the mean T½γ for the MR formulation was16.6 hours. Similar values of terminal elimination half-life werepreviously reported in the literature. Pilbrant A., et al., Eur. J.Clin. Pharmacol (1981), 20: 65-72.

Following a single oral dose of 1.3 g of the MR formulation, the meanplasma concentrations of tranexamic acid observed at 28, 32, and 36hours were 0.19724, 0.15672, and 0.13624 mcg/mL, respectively.Considering the therapeutic window of tranexamic acid (5-15 mcg/mL) andthe very low plasma concentration levels observed at these timepoints,the terminal elimination half-life (T½γ) characterizing the slow declineof plasma concentrations should not play a clinically significant rolein the frequency of drug administration.

Pharmacokinetic Conclusions

The pharmacokinetic linearity results indicate that the ratios ofleast-squares means of AUCτ (Day 7) to AUCinf (Day 1) and the 90%confidence interval for the MR formulation were within the 80-125%acceptance range. Based on these results, the 650 mg tranexamic acidmodified release tablets exhibited linear pharmacokinetics followingrepeated administration (7 days) of a 1.3 g dose under fastingconditions.

Steady-state plasma concentrations of tranexamic acid for themodified-release tablets were reached on Day 4 (−72-hour), since thep-value for the first contrast was not statistically significant at a 5%alpha error.

The pharmacokinetics of tranexamic acid was properly described using athree compartment PK model with linear elimination. The absorptionkinetic of the single-dose (Day 1) data of tranexamic acid for the MRformulation was best described using a mixed-order rate constant ofabsorption.

Plasma Pharmacokinetic Parameters for the modified release (MR)formulation of Tranexamic Acid on day 1 are listed in Table 21 below.

TABLE 21 In In AUC_(0-t)* AUC_(inf)* Half- (mcg · (mcg · In C_(max)*T_(max) life K_(el) h/ml) h/ml) (mcg/ml) (h) (h) (1/h) Mean 74.57176.875 13.176041 3.079 11.078 0.06443 CV % 31.3 30.4 33.1 25.0 16.9 18.3N 19 19 19 19 19 19 *For In-transformed parameters, the antilog of themean (i.e. the geometric mean) is reported; AUC_(0-t) = AUC post dose(0-36 hours)

Plasma Pharmacokinetic Parameters for the modified release (MR)formulation of Tranexamic Acid on day 7 are listed in Table 22 below.

TABLE 22 In AUC_(τ)* Flux Flux (mcg · In C_(max)* In C_(min)* T_(max)1** 2** h/ml) (mcg/mL) (mcg/ml) (h) (%) (%) Mean 74.791 15.8035095.157681 2.553 113.16 219.21 CV % 29.0 30.1 31.2 14.4 21.6 44.6 N 19 1919 19 19 19 *For In-transformed parameters, the antilog of the mean(i.e. the geometric mean) is reported; AUC_(τ) = AUC dosing interval (8hours) **Defined in Table 16

CONCLUSION

While the invention herein disclosed has been described by means ofspecific embodiments and applications thereof, numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the spirit and scope of the present invention. Suchmodifications are understood to be within the scope of the appendedclaims.

What is claimed is:
 1. A tranexamic acid formulation comprising:tranexamic acid or a pharmaceutically acceptable salt thereof; and amodified release material; wherein the tranexamic acid orpharmaceutically acceptable salt thereof is present in an amount fromabout 50% to about 95% by weight of the formulation; wherein themodified release material is present in an amount from about 5% to about50% by weight of the formulation; and wherein said formulation providesan in-vitro dissolution release rate of the tranexamic acid orpharmaceutically acceptable salt thereof, when measured by a USP 27Apparatus Type II Paddle Method @50 RPM in 900 ml water at 37±0.5° C.,of less than about 40% by weight of the tranexamic acid orpharmaceutically acceptable salt thereof released at about 15 minutes,less than about 70% by weight of the tranexamic acid or pharmaceuticallyacceptable salt thereof released at about 45 minutes and not less thanabout 50% by weight of the tranexamic acid or pharmaceuticallyacceptable salt thereof released at about 90 minutes.
 2. The formulationof claim 1, wherein said formulation provides an in-vitro dissolutionrelease rate of the tranexamic acid or pharmaceutically acceptable saltthereof, when measured by the USP 27 Apparatus Type II Paddle Method @50RPM in 900 ml water at 37±0.5° C., of about 0% to about 40% by weight ofthe tranexamic acid or pharmaceutically acceptable salt thereof releasedat about 15 minutes, from about 20% to about 60% by weight of thetranexamic acid or pharmaceutically acceptable salt thereof released atabout 30 minutes, from about 40% to about 65% by weight of thetranexamic acid or pharmaceutically acceptable salt thereof released atabout 45 minutes, from about 50% to about 95% by weight of thetranexamic acid or pharmaceutically acceptable salt thereof released atabout 60 minutes, and not less than about 60% by weight of thetranexamic acid or pharmaceutically acceptable salt thereof released atabout 90 minutes.
 3. The formulation of claim 1, wherein the formulationreleases about 10% to about 25% by weight of the tranexamic acid orpharmaceutically acceptable salt thereof every 15 minutes when measuredin vitro utilizing the USP 27 Apparatus Type II Paddle Method @50 RPM in900 ml water at 37±0.5° C.
 4. The formulation of claim 1, wherein theformulation releases about 1% of the tranexamic acid or pharmaceuticallyacceptable salt thereof every minute when measured in-vitro utilizingthe USP 27 Apparatus Type II paddle method at 50 RPM in 900 ml water at37±0.5° C.
 5. The formulation of claim 1, wherein the tranexamic acid orpharmaceutically acceptable salt thereof is tranexamic acid.
 6. Theformulation of claim 1, wherein a mean maximum plasma concentration(C_(max)) of tranexamic acid of from about 5 to about 17.5 mcg/ml isprovided following administration of two oral dosage forms of theformulation, each providing a dose of about 650 mg of tranexamic acid.7. The formulation of claim 1, wherein the formulation is in the form ofan oral dosage form.
 8. The formulation of claim 8, wherein the oraldosage form provides a dose of about 650 mg of tranexamic acid.
 9. Theformulation of claim 9, wherein the tranexamic acid or pharmaceuticallyacceptable salt thereof is tranexamic acid.
 10. The formulation of claim1, wherein the formulation is in the form of a matrix tablet whichcomprises a drug mixed together with a granulated modified releasematerial.
 11. The formulation of claim 10, wherein the tablet provides adose of about 650 mg of tranexamic acid.
 12. The formulation of claim11, wherein the tranexamic acid or pharmaceutically acceptable saltthereof is tranexamic acid.
 13. The formulation of claim 1, wherein thetranexamic acid or pharmaceutically acceptable salt thereof is presentin an amount from about 60% to about 90% by weight of the formulation.14. The formulation of claim 1, wherein the tranexamic acid orpharmaceutically acceptable salt thereof is present in an amount fromabout 60% to about 80% by weight of the formulation.
 16. The formulationof claim 1, wherein the modified release material is present in anamount from about 10% to about 35% by weight of the formulation.
 17. Theformulation of claim 1, wherein: the tranexamic acid or pharmaceuticallyacceptable salt thereof is present in an amount from about 60% to about90% by weight of the formulation; the modified release material ispresent in an amount from about 10% to about 35% by weight of theformulation; the formulation is in the form of a matrix tablet whichcomprises a granulated drug mixed together with the modified releasematerial and the tablet provides a dose of about 650 mg of tranexamicacid.
 18. The formulation of claim 17, wherein the tranexamic acid orpharmaceutically acceptable salt thereof is tranexamic acid.
 19. Amethod of treating menorrhagia comprising administering to a patient inneed of such treatment the tranexamic acid formulation of claim 1,wherein the formulation is in the form of at least one oral dosage form,each providing a dose of about 650 mg of tranexamic acid.
 20. A methodof treating menorrhagia comprising administering to a patient in need ofsuch treatment the tranexamic acid formulation of claim 1, wherein theformulation is in the form of at least one matrix tablet which comprisesa granulated drug mixed together with the modified release material andeach tablet provides a dose of about 650 mg of tranexamic acid.